A novel tricarbonylmethane agent (CMC2.24) reduces human pancreatic tumor growth in mice by targeting Ras

Abstract

Pancreatic Cancer (PC) is a deadly disease in need of new therapeutic options. We recently developed a novel tricarbonylmethane agent (CMC2.24) as a therapeutic agent for PC, and evaluated its efficacy in preclinical models of PC. CMC2.24 inhibited the growth of various human PC cell lines in a concentration and time-dependent manner. Normal human pancreatic epithelial cells were resistant to CMC2.24, indicating selectivity. CMC2.24 reduced the growth of subcutaneous and orthotopic PC xenografts in mice by up to 65% (P < 0.02), and the growth of a human patient-derived tumor xenograft by 47.5% (P < 0.03 vs vehicle control). Mechanistically, CMC2.24 inhibited the Ras-RAF-MEK-ERK pathway. Based on Ras Pull-Down Assays, CMC2.24 inhibited Ras-GTP, the active form of Ras, in MIA PaCa-2 cells and in pancreatic acinar explants isolated from Kras mutant mice, by 90.3% and 89.1%, respectively (P < 0.01, for both). The inhibition of active Ras led to an inhibition of c-RAF, MEK, and ERK phosphorylation by 93%, 91%, and 87%, respectively (P < 0.02, for all) in PC xenografts. Furthermore, c-RAF overexpression partially rescued MIA PaCa-2 cells from the cell growth inhibition by CMC2.24. In addition, downstream of ERK, CMC2.24 inhibited STAT3 phosphorylation levels at the serine 727 residue, enhanced the levels of superoxide anion in mitochondria, and induced intrinsic apoptosis as shown by the release of cytochrome c from the mitochondria to the cytosol and the further cleavage of caspase 9 in PC cells. In conclusion, CMC2.24, a potential Ras inhibitor, is an efficacious agent for PC treatment in preclinical models, deserving further evaluation.

Targeting Glycolysis with Epigallocatechin-3-Gallate Enhances the Efficacy of Chemotherapeutics in Pancreatic Cancer Cells and Xenografts

“…Whole cell protein lysates were prepared, and electrophoresis and electroblotting were performed as previously described [31]. Membranes were probed overnight with the following primary antibodies (1:1000 dilution) from Cell Signaling Technology (Danvers, MA, USA): PFKP (Cat #8164), PKM2 (Cat #4053), HK2 (Cat #2867), LDHA (Cat #3582), phospho-Chk1 (Ser345) (Cat #2348), phospho-p53 (Ser15) (Cat #9286), p53 (Cat #2527), p21 Waf1/Cip1 (Cat #2947), cdc2 (Cat #28439), Cyclin B1 (Cat #12231), Caspase-3 (Cat #14220), Caspase-7 (Cat #12827), Caspase-9 (Cat #9508), and PARP (Cat #9542).…”

Periodontal therapeutics: Current host‐modulation agents and future directions

“…Of particular interest, Mackenzie's group at Stony Brook's Cancer Center recently demonstrated that chemically modified curcumin-2.24 induced apoptosis in pancreatic cancer cells and reduced pancreatic tumor growth by inhibiting active Ras and signal transducer and activator of transcription-3 phosphorylation. 135 Moreover, even at high (1000 mg/kg) oral doses, the animals treated with chemically modified curcumin-2.24 showed no evidence of toxicity (Heta Bhatt et al, unpublished data). As reviewed recently by Mendes et al, 136 the subset of sirtuins that are of particular relevance to periodontal disease include 7 proteins (sirtuins 1-7) with different subcellular locations, mitochondria, cytoplasm, or nucleus.…”

“…Wright et al reported that in a mouse model of medulloblastoma, treatment with chemically modified curcumin‐2.24 combined with a curcumin‐phosphatidyl choline (to improve bioavailability) showed therapeutic efficacy in controlling tumor growth. Of particular interest, Mackenzie's group at Stony Brook's Cancer Center recently demonstrated that chemically modified curcumin‐2.24 induced apoptosis in pancreatic cancer cells and reduced pancreatic tumor growth by inhibiting active Ras and signal transducer and activator of transcription‐3 phosphorylation . Moreover, even at high (1000 mg/kg) oral doses, the animals treated with chemically modified curcumin‐2.24 showed no evidence of toxicity (Heta Bhatt et al, unpublished data).…”

“…reduced pancreatic tumor growth by inhibiting active Ras and signal transducer and activator of transcription-3 phosphorylation 135. Moreover, even at high (1000 mg/kg) oral doses, the animals treated with chemically modified curcumin-2.24 showed no evidence of toxicity (Heta Bhatt et al, unpublished data).7 | FUTURE HOS T-MODUL ATION C AND IDATE S FOR CLINI C AL APPLI C ATI ONSeveral additional host modulators have also demonstrated potential therapeutic value based on in vitro studies and animal studies but have not yet reached the stage of development to justify randomized clinical trials.…”

Novel Chemically Modified Curcumin (CMC) Derivatives Inhibit Tyrosinase Activity and Melanin Synthesis in B16F10 Mouse Melanoma Cells

“…Our group has reported on CMC2.24, a triketonic N -phenylaminocarbonyl derivative of bis-demethoxycurcumin, which exhibits enhanced stability and solubility compared to curcumin and has emerged as a ‘lead compound’ for several pharmacological applications such as treatment of anthrax by inhibition of the metalloprotease, lethal factor [ 21 ], treatment of cancers of the pancreas [ 22 ] and prostate [ 23 ], normalizing wound healing in diabetic rats [ 24 ], reduction in severity of periodontitis and inhibition of alveolar bone resorption associated with the disease in a rat model [ 25 , 26 ]. In addition, CMC2.24 has shown superior anti-inflammatory activity compared to the parent compound curcumin, in inhibiting periodontitis-induced bone resorption in rats via multiple mechanisms [ 27 ], and most recently, for the treatment of natural periodontitis in beagle dogs [ 28 , 29 ].…”